Choroidal thickness changes in systemic lupus erythematosus patients

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O R I G I N A L R E S E A R C H

Choroidal thickness changes in systemic lupus

erythematosus patients

This article was published in the following Dove Press journal: Clinical Ophthalmology

Arnaldo Dias-Santos1–3 Joana Tavares Ferreira1–3 Soﬁa Pinheiro4

João Paulo Cunha1,3 Marta Alves5

Ana Luísa Papoila3,5,6 Maria Francisca Moraes-Fontes3,7,8 Rui Proença9,10

1_{Department of Ophthalmology, Centro}

Hospitalar e Universitário de Lisboa Central, Lisbon, Portugal;2_Department

of Ophthalmology, Hospital CUF Descobertas, Lisbon, Portugal;3_NOVA

Medical School, Universidade NOVA de Lisboa, Lisbon, Portugal;4_Autoimmune

Disease Unit, Unidade de Doenças Auto-imunes/serviço Medicina 3, Hospital de Santo António Dos Capuchos, Centro Hospitalar e Universitário de Lisboa Central, Lisbon, Portugal;5_Epidemiology

and Statistics Unit, Research Center, Centro Hospitalar e Universitário de Lisboa Central, Lisbon, Portugal;6_CEAUL

(Center of Statistics and Applications), Lisbon University, Lisbon, Portugal;

7_{Autoimmune Disease Unit, Unidade de}

Doenças Auto-imunes/serviço de Medicina 7.2, Hospital Curry Cabral, Centro Hospitalar e Universitário de Lisboa Central, Lisbon, Portugal;

8_{Instituto Gulbenkian de Ciência, Oeiras,}

Portugal;9_{Department of}

Ophthalmology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal;10_{Faculty of Medicine,}

University of Coimbra, Coimbra, Portugal

Purpose: To compare choroidal thickness (CT) between patients with systemic lupus erythematosus (SLE) without ophthalmologic manifestations and a control group. To study the effects in CT of disease duration, activity index, medication and systemic comorbidities. Methods: Cross-sectional study where spectral-domain optical coherence tomography with enhanced depth imaging was used to measure CT in 13 locations, subfoveally and at 500-µm intervals along a horizontal and a vertical section from the fovea. Linear regression models were used.

Results: Sixty-eight SLE patients andﬁfty healthy controls were enrolled. CT multivariable

analysis revealed lower values in SLE patients (12.93–26.73 µm thinner) in all locations,

except the inferior quadrants (6.48–10.44 µm thicker); however, none of these results

reached statistical signiﬁcance. Contrary to the control group, the normal topographic

varia-tion in CT between macular quadrants and from the center to the periphery was not observed

in the SLE group. Multivariable analysis in the SLE group alone revealed a signiﬁcant

negative association with anticoagulants (50.10–56.09 µm thinner) and lupus nephritis

(40.79–58.63 µm thinner). Contrary to controls, the CT of SLE patients did not respond to

changes in mean arterial pressure.

Conclusion: CT in SLE appears to be thinner, particularly in the subset of patients with nephritis and taking anticoagulants, suggesting more advanced systemic vascular disease. Choroidal responses to hemodynamic changes may also be altered in SLE.

Keywords: choroidal thickness, enhanced depth imaging, spectral domain optical coherence tomography, systemic lupus erythematosus

Introduction

Systemic lupus erythematosus (SLE) is a chronic, autoimmune, connective tissue disease that can involve multiple organ systems. Similar to other autoimmune disorders, it can affect the vascular system in multiple territories either directly by inducing vasculitis and an increased atherosclerotic or thrombotic burden or indirectly by interfering with normal vasoregulatory mechanisms.1–4 Up to one-third of SLE patients present ocular manifestations, which may precede extraocular systemic disease.5In the eye, SLE can affect almost any structure, including the vascular supply of the retina, the choroid and the optic nerve head.6 Lupus choroidopathy is rare and can present with serous retinal detachment, retinal pigment epithelium detachment, retinal pigment epitheliopathy, choroidal ischemia or effusion.5When present, lupus choroidopathy is usually a marker of high disease activity and often associated with the central nervous system and renal disease.7On the other hand, subtle and subclinical changes in choroidal circulation have been Correspondence: Arnaldo Dias-Santos

Serviço de Oftalmologia, Hospital de Santo António dos Capuchos, Alameda de Santo António dos Capuchos, Lisboa 1169-050, Portugal

Tel +351 21313 6492

Email [email protected]

Clinical Ophthalmology

Dove

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described in patients with lupus nephritis.8 These facts raise the hypothesis that choroidal vascular bed may be affected early in the course of the disease, possibly re ﬂect-ing existﬂect-ing microvasculopathy in other organ systems.

Spectral domain optical coherence tomography (SD-OCT) with enhanced depth imaging (EDI) software is a noninvasive imaging modality that provides high-resolu-tion three-dimensional images of the retina and choroid.9 In recent years, this technique enabled us to characterize the morphology and thickness of the choroid in several ocular and systemic pathologies.10–12 However, only a very limited number of publications have evaluated the choroid in SLE patients using EDI SD-OCT.13–16 These studies had heterogeneous samples and presented contra-dictory results.

In this study, we compared choroidal thickness (CT) using SD-OCT between SLE patients without ophthalmo-logic manifestations and a control group in whom systemic autoimmune diseases were excluded. We also studied the relationship between CT and, among others, disease dura-tion, disease activity score, hydroxychloroquine intake and cumulative dosage, systemic medications and systemic comorbidities frequently present in SLE patients, namely, lupus nephritis, neuropsychiatric SLE (NP-SLE), Sjogren’s syndrome and anti-phospholipid syndrome.

Materials and methods

Subject groups

This was a cross-sectional study nested in a prospective cohort study that is still ongoing. The study was conducted at the Ophthalmology Department and at the Autoimmune Disease Unit of the Central Lisbon Hospital and University Center. The study occurred between July 2017 and August 2018. Consecutive SLE patients sent by the Autoimmune Disease Unit for ophthalmological screening were observed for inclusion/exclusion criteria. Patients fulﬁlled the 1997 revised American College of Rheumatology (ACR) criteria for the diagnosis of SLE17and were aged between 18 and 80 years old. Only those without signs of optic neuropathy, retinopathy or choroidopathy were included in the study.

The control group, in whom rheumatologic diseases were excluded, was recruited from the General Ophthalmology Department.

The exclusion criteria were a refractive error >5 diop-ters or/and axial length >25 mm in the studied eye, keratic astigmatism >3 diopters, diabetes mellitus, pregnancy, signs or previous history of optic neuropathy, retinopathy

or choroidopathy (namely, lupus-related, age-related macular degeneration, vascular occlusion, macular dystro-phy, hydroxychloroquine retinopathy, glaucoma, ocular hypertension or neurodegenerative diseases, such as Alzheimer’s or Parkinson’s disease), ocular tumor, pre-vious episodes of intraocular inﬂammation, history of intraocular or refractive surgery and signiﬁcant media opacities that precluded fundus imaging.

The Institutional Ethics Committee approved the study, and written informed consent was obtained from all parti-cipants. The tenets of the Declaration of Helsinki were respected.

Study procedures

All patients underwent a prescreening visit where demo-graphic, background medical history, full ophthalmological examination with visual acuity, anterior segment examina-tion, Goldmann applanation tonometry, dilated fundus examination and optic biometry (using Lenstar LS 900®, Haag-Streit AG, Koeniz, Switzerland) were recorded. After this visit, patients were assigned to a specific study visit where SD-OCT was performed. Blood pressure (BP) was also measured before SD-OCT. SLE patients currently or previously treated with hydroxychloroquine also underwent fundus autofluorescence imaging and 10–2 macular auto-mated threshold visualfield testing to exclude retinal toxicity according to the American Academy of Ophthalmology recommendations.18An evaluation by an autoimmune dis-ease specialist was also performed in all SLE patients, including a complete physical examination and laboratory tests required to access disease activity state and systemic involvement. Disease activity was scored using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).19 One eye per patient was randomly selected for the study.

Visual acuity

Best corrected distance visual acuity (BCVA) was evalu-ated for each eye using Snellen charts. The value was then converted to the logarithm of the minimum angle of reso-lution (LogMAR).

Intraocular pressure

Before pupillary dilation, intraocular pressure was mea-sured using Goldmann applanation tonometry, and a mean of 3 measurements was recorded.

Mean arterial pressure

The BP was measured using an automatic sphygmoman-ometer in the left arm in the seated position. Systolic

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(SBP) and diastolic (DBP) blood pressures were recorded, and the mean arterial pressure (MAP) was calculated according to the following formula:

MAP¼ DBP þ 1=3 SBP DBPð Þ

Imaging

All patients were examined with SD-OCT (Spectralis® Heidelberg Engineering, Heidelberg, Germany). Scans were performed in the EDI mode using a previously described method.9 Twenty-ﬁve sections, each comprising 100 aver-aged scans, were obtained in a 20×20⁰ (5.8 mm×5.8 mm) square centered on the fovea. All OCT examinations were performed by an ophthalmologist (J.T.F.) and were assessed by another ophthalmologist (A.D.S.); both were masked to the patients’ diagnosis. All scans were performed between 2 PM and 4 PM. CT was measured perpendicularly from the outer border of the hyperreﬂective line corresponding to the retinal pigment epithelium (RPE) to the inner scleral border. These measurements were taken at the subfoveal choroid and at 500-µm intervals from the fovea to 1500 µm temporal, 1500 µm nasal, 1500 µm superior and 1500 µm inferior (13 locations) (Figure 1).

Statistical evaluation

First, an exploratory analysis was performed for all variables. Categorical variables were presented as frequencies (percen-tages), and continuous variables were presented as the mean (standard deviation [SD]) or median and interquartile range (25th percentile–75th percentile). Nonparametric Chi-Square test and Mann-Whitney test were used. To study progressive CT decrease from the center to the periphery, Friedman test was applied. Linear regression models were used to identify the variables that explain the variability of CT in the SLE and control groups. The variables gender, age, BMI, IOP, axial length, spherical equivalent, MAP, BCVA, and

pharmacological variables were considered for these analyses. A second study for the SLE group alone was performed also using linear regression models and scatterplots with locally weighted scatterplot smoothers. Disease duration, disease activity score, hydroxychloroquine intake and cumulative dosage, systemic medications, and other comorbidities fre-quently present in these patients were added to this analysis.

Those variables attaining a p-value <0.25 in the uni-variable analyses were selected as candidates for the multi-variable models. Normality assumption of the residuals was veriﬁed using Shapiro-Wilk test. Given the multiple testing inherent to this study, Bonferroni corrections were applied. A level of signiﬁcance α=0.05 was considered. Data were analyzed using the Statistical Package for the Social Science for Windows (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp.).

Results

Patient demographics and clinical

characteristics

A total of 68 eyes of 68 SLE patients (58 women and 10 men) and 50 eyes of 50 healthy controls (43 women and 7 men) were enrolled in this study. The median duration of SLE diagnosis was 11.0 (6.25–19.00) years, and 26 patients (38.8%) had active disease (SLEDAI >3) at the time of the study visit. Among SLE patients, 19 (27.9%) had NP-SLE, including 16 with the central type and 3 with the peripheral type; 18 (26.5%) had biopsy-proven lupus nephritis; 21 (30.9%) had anti-phospholipid syndrome; and 5 patients (7.4%) had Sjogren’s syndrome. Demographic and clinical characterization of the two groups is summarized inTable 1. Pharmacological history of patients and controls, except for hydroxychloroquine (HCQ), is presented inTable 2.

Figure 1 Choroidal thickness measurements were made in the subfoveal choroid and at 500-µm intervals from the fovea to 1500 µm temporal, 1500 µm nasal, 1500 µm superior and 1500 µm inferior (13 locations).

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Enhanced depth imaging optical

coherence tomography

Comparison of CT between groups in all 13 study loca-tions is depicted inTable 3. CT is generally higher in the control group except in the inferior quadrants, particularly at 1000 and 1500 µm inferior to the fovea. However, these differences did not reach statistical signiﬁcance. The over-all distribution of CT in the four quadrants showed differ-ent patterns between groups. The choroid in the superior quadrants is thicker than the inferior choroid in the control group. In the SLE group, this relationship is reversed. Regarding the temporal-nasal relationship, both groups presented a thicker choroid in the temporal quadrants. In addition, a normal progressive decrease in CT from the

center to the periphery was observed in the horizontal meridian for both groups (p<0.05). However, regarding the vertical meridian, this progressive decrease was not observed in the SLE group (p>0.05).

In multivariable regression models, after correcting for gender, age, BMI, MAP, BCVA, IOP, spherical equivalent, axial length and medication, CT in SLE patients was lower in all locations, except for the inferior quadrants (1000 µm and 1500 µm inferior to the fovea) where it was higher (Table 4). However, evidence of a difference was exclu-sively found in the temporal 1500-µm location (regression coefﬁcient estimate: −26.73; 95% conﬁdence interval: −53.40 to −0.05; p=0.050); however, after applying Bonferroni adjustment for multiple testing, the result was

Table 1 Demographic and clinical characteristics of the patients by group

Variables SLE group (n=68) Control group (n=50) p

Age, years 45.50 (12.67) 52.76 (14.45) 0.003

Female gender, n (%) 58 (85.3) 43 (86) 0.914*

Body Mass Index, Kg/m2 24.64 (3.91) 25.79 (3.73) 0.07

BCVA, LogMAR 0.010 (0.051) 0.005 (0.020) 0.89

IOP-Goldmann, mm Hg 13.60 (2.88) 13.76 (2.55) 0.738

Spherical Equivalent, D −0.25 (−1.0–0.25) 0.13 (−0.63–1.0) 0.048

Axial Length, mm 23.56 (1.00) 22.89 (0.96) <0.001

MAP, mm Hg 88.71 (11.06) 91.92 (13.11) 0.114

SLE duration, years 11.0 (6.25–19.0) NA

SLEDAI 2 (0–4) NA

HCQ

Daily dose, mg 329 (96) NA

Cumulative Dose, g 778 (228.1–1606.0) NA

Therapy duration, years 5.30 (1.81–11.83) NA

Daily dose/weight, mg/kg 5.02 (1.61) NA Cumulative dose/weight, g/kg 10.76 (3.16–25.47) NA NP-SLE, n (%) 19 (27.9) NA Central NP-SLE, n (%) 16 (23.5) NA Peripheral NP-SLE, n (%) 3 (4.4) NA Lupus nephritis, n (%) 18 (26.5) NA Anti-phospholipid syndrome, n (%) 21 (30.9) NA Sjogren’s syndrome, n (%) 5 (7.4) NA

Notes: For continuous variables, results are expressed as mean (SD) or median (interquartile range), as appropriate. *Chi-square test, remaining p-values were obtained by Mann-Whitney test.

Abbreviations : BCVA, best corrected visual acuity; HCQ, hydroxychloroquine; IOP, intraocular pressure; logMAR, logarithm of the minimum angle of resolution; MAP, mean arterial pressure; NA, not applicable; NP-SLE, neuropsychiatric systemic lupus erythematosus; SLE, systemic lupus erythematosus; SLEDAI, Systemic Lupus Erythematosus Disease Activity Index.

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not statistically signiﬁcant. Therefore, there is only a ten-dency for a lower CT in SLE patients (−1.35 to −26.73 µm) in subfoveal, superior, nasal and temporal quadrants and at 500 µm inferior to the fovea and a tendency for higher CT in the 1000 µm and 1500 µm inferior to the fovea (6.48 to 10.44 µm). Independently from the group, age and axial length were negatively associated with CT (there was a mean decrease in CT between 20.63 and 35.62 µm for each 10 additional

years and a mean decrease of 23.90 to 37.85 µm for each additional 1 mm in axial length) in all locations. CT was negatively associated with MAP at 1000 µm nasal, 500 µm and 1000 µm inferior, 500 µm and 1000 µm temporal to the fovea (there was a mean decrease of 1.26 to 1.48 µm for each increase of one mmHg). Finally, CT was negatively associated with BMI at 500 µm, 1000 µm, 1500 µm superior and 1500 µm temporal to the fovea (with a mean decrease of 4.21 to 4.96 µm in the CT for each increase of one kg/m2in BMI).

A multivariable regression analysis was also performed for the SLE group alone (Table 5). Age and axial length maintained a negative association with CT for all loca-tions. Anticoagulants presented a negative association with CT in the subfoveal and 500 µm inferior to the fovea locations (CT was 50.10 and 56.09 µm thinner, respec-tively, in patients taking anticoagulants). Sjogren’s syn-drome was associated with a thicker choroid in the 1000 µm superior location (CT was 73.07 µm thicker). Corticotherapy showed a negative association with CT at 1500 µm temporal from the fovea (with a 2.43 µm decrease in CT for each one mg increase of prednisone equivalent). Diuretics also presented a negative association with CT at 1000 µm superior to the fovea (in patients taking diuretics CT was 85.44 µm thinner). Finally, lupus nephritis revealed a negative association with CT at 500 µm, 1000 µm and 1500 µm nasal, 500 µm, 1000 µm

Table 2 Pharmacological history of the patients by group

Variables SLE group (n=68) Control group (n=50) p

Systemic steroids 31 (45.6) 0

-Mean daily dose PDN equivalent (SD), mg 10.1 (60.5) NA

-Other immunosuppressives 26 (38.2) 0

-Biological agents 7 (10.3) 0

-ACE inhibitor 10 (14.7) 3 (6) 0.136

Angiotensin II receptor antagonist 8 (11.8) 3 (6) 0.351

Beta blocker 8 (11.8) 3 (6) 0.351

Diuretics 4 (5.9) 3 (6) 1.000

Calcium channel blocker 6 (8.8) 0 0.038

Statins 10 (14.7) 17 (34) 0.014

Nitrates 0 1 (2) 0.424

Antiplatelet therapy 17 (25) 1 (2) 0.001

Anticoagulant 12 (17.6) 0 0.002

Thyroid hormones 7 (10.3) 1 (2) 0.136

Selective serotonin reuptake inhibitor 10 (14.7) 2 (4) 0.057

Tricyclic antidepressant 3 (4.4) 0 0.261

Benzodiazepines 8 (11.8) 2 (4) 0.187

Notes: Results are expressed as n (%). p-values were obtained by chi-square test or Fisher’s exact test, as appropriate. Abbreviations: ACE, angiotensin-converting-enzyme; NA, not applicable; PDN, prednisone; SLE, systemic lupus erythematosus.

Table 3 Choroidal thickness (µm) at 13 locations by group

Location SLE group

(n=68) Control group (n=50) p Subfoveal central µm 282.22 (83.71) 297.88 (84.65) 0.320 Temporal 500 µm 268.66 (75.77) 291.18 (78.10) 0.118 Temporal 1000 µm 261.35 (74.61) 280.46 (77.41) 0.179 Temporal 1500 µm 246.74 (75.18) 267.46 (81.38) 0.156 Nasal 500 µm 267.00 (81.66) 280.04 (88.56) 0.411 Nasal 1000 µm 251.40 (79.36) 265.62 (85.10) 0.353 Nasal 1500 µm 225.90 (75.37) 243.38 (88.09) 0.249 Superior 500 µm 280.75 (86.21) 292.78 (78.24) 0.438 Superior 1000 µm 275.53 (78.20) 285.40 (81.27) 0.506 Superior 1500 µm 274.97 (75.36) 287.04 (78.82) 0.401 Inferior 500 µm 278.82 (87.61) 279.14 (82.47) 0.984 Inferior 1000 µm 280.69 (78.08) 272.76 (80.48) 0.591 Inferior 1500 µm 282.53 (83.79) 271.46 (79.43) 0.470

Notes: Results are expressed as mean (SD). p-values were obtained by univariable linear regression models.

Abbreviation: SLE, systemic lupus erythematosus.

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Table 4 Results of choroidal thickness multivariable regression models

Model Coefﬁcient estimate 95% conﬁdence interval p

Dependent variable: CT subfoveal central

SLE group −16.17 −45.12 to 12.79 0.271

Age (years) −30.28 −42.01 to −20.15 <0.001

Axial length (mm) −31.45 −47.99 to −18.18 <0.001

Dependent variable: CT 500 µm superior

SLE group −14.87 −42.98 to 13.23 0.297

Age (years) −24.97 −36.18 to −13.76 <0.001

Body mass index (Kg/m2) −4.96 −8.62 to −1.30 0.008

SLE group −12.93 −39.23 to 13.375 0.332

Age (years) −25.79 −36.29 to −15.298 <0.001

SLE group −16.64 −43.44 to 10.16 0.221

Age (years) −20.63 −31.32 to −9.94 <0.001

Axial length (mm) −23.90 −37.68 to −10.118 0.001

Body mass index (Kg/m2₎ _−4.83 _{−8.32 to −1.34} _0.007

Dependent variable: CT 500 µm nasal

SLE group −13.61 −42.58 to 15.36 0.354

Age (years) −32.02 −42.96 to −21.09 <0.001

SLE group −13.88 −40.95 to 13.19 0.312

Age (years) −27.74 −38.84 to −16.64 <0.001

MAP (mm Hg) −1.30 −2.51 to −0.09 0.036

SLE group −18.00 −45.02 to 9.02 0.190

Age (years) −32.57 −42.77 to −22.37 <0.001

Dependent variable: CT 500 µm temporal

SLE group −21.94 −48.14 to 4.27 0.100

Age (years) −23.10 −33.85 to −12.36 <0.001

MAP (mm Hg) −1.30 −2.51 to −0.09 0.036

SLE group −19.98 −46.09 to 6.14 0.132

Age (years) −21.51 −32.22 to −10.81 <0.001

MAP (mm Hg) −1.30 −2.51 to −0.09 0.036

SLE group −26.73 −53.40 to −0.05 0.050

Age (years) −24.63 −35.27 to −13.98 <0.001

(Continued)

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Table 4 (Continued).

Model Coefﬁcient estimate 95% conﬁdence interval p

Dependent variable: CT 500 µm inferior

SLE group −1.35 −30.63 to 27.93 0.927

Age (years) −25.70 −37.71 to −13.70 <0.001

MAP (mm Hg) −1.30 −2.51 to −0.09 0.036

SLE group 6.48 −19.16 to 32.11 0.618

Age (years) −28.97 −39.48 to −18.46 <0.001

MAP (mm Hg) −1.26 −2.41 to −0.12 0.031

SLE group 10.44 −15.95 to 36.83 0.435

Age (years) −35.62 −45.58 to −25.66 <0.001

Note: Age: for each 10 years increase.

Abbreviations: CT, choroidal thickness; MAP, mean arterial pressure; SLE, systemic lupus erythematosus. p-values were obtained by linear regression models.

Table 5 Results of choroidal thickness multivariable regression models for SLE group

Model Coefﬁcient estimate 95% conﬁdence interval P

Dependent variable: CT subfoveal central

Age (years) −27.35 −42.57 to −12.14 0.001

Anticoagulant −50.10 −97.09 to −3.12 0.037

Age (years) −30.76 −46.20 to −15.32 <0.001

Nephritis −56.55 −98.17 to −14.92 0.009

Age (years) −17.34 −31.78 to −2.91 0.019

Nephritis −40.79 −78.14 to −3.45 0.033

Sjogren 73.07 9.64 to 136.51 0.025

Body mass index (Kg/m2₎ _−4.99 _{−9.64 to −0.34} _0.036

Diuretics −85.44 −158.01 to −12.86 0.022

Age (years) −18.08 −32.99 to −3.17 0.018

Axial length (mm) −22.09 −40.93 to-3.25 0.022

Age (years) −29.04 −43.58 to −14.50 <0.001

Nephritis −58.63 −97.83 to −19.42 0.004

Age (years) −29.94 −43.84 to −16.04 <0.001

Nephritis −50.67 −88.14 to −13.20 0.009

(Continued)

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superior and 1500 µm inferior to the fovea (with a mean decrease in CT of 40.79 to 58.63 µm in patients with lupus nephritis). However, apart from axial length and age, after applying Bonferroni corrections, statistical signiﬁcance was only observed for lupus nephritis in the 500 µm nasal location. CT was not statistically associated with disease duration, MAP, SLEDAI, NP-SLE, anti-phospho-lipid syndrome or HCQ treatment duration or dosage. However, it is possible to document a constant pattern of CT distribution according to disease duration in SLE patients. In all 13 locations, CT remains stable through the ﬁrst 20 years of disease and then starts to decrease slightly with time (Figure 2).

Regarding MAP, there is a different CT response between groups. In the control group, there is a reduction of CT with increasing MAP in all locations, showing stabilization for higher MAP-values (greater than

100 mmHg), while CT does not change throughout the whole range of MAP in SLE (eg, seeFigure 3for location 500 µm nasal).

Discussion

The choroid is the tissue with the highest blood ﬂow per unit of weight and plays a key role in the nutrition and homeostasis of the outer layers of the retina.20 On the other hand, it may be a target and reﬂect the microvasculature damage of systemic vascular pathol-ogies. For example, systemic arterial hypertension has been associated with choroidal thinning,21 while dia-betes mellitus induces choroidal thickening in an early phase before the development of diabetic retinopathy.22 Coronary heart disease is also associated with a decrease in CT independently of diabetes mellitus or systemic hypertension.23

Table 5 (Continued).

Model Coefﬁcient estimate 95% conﬁdence interval P

Age (years) −27.76 −40.96 to −14.56 <0.001

Nephritis −51.06 −86.64 to −15.48 0.006

Age (years) −23.44 −37.88 to −9.00 0.002

Age (years) −22.79 −37.11 to −8.48 0.002

Age (years) −32.89 −46.85 to −18.93 <0.001

Corticosteroids (mg) −2.44 −4.38 to −0.50 0.015

Age (years) −28.48 −44.59 to −12.37 0.001

Anticoagulant −56.09 −105.84 to −6.34 0.028

Age (years) −31.52 −45.58 to −17.46 <0.001

Age (years) −35.425 −49.71 to −21.12 <0.001

Nephritis −53.58 −92.12 to −15.05 0.007

Note: Age: for each 10 years increase. Corticosteroids dose is expressed in prednisone equivalent (mg). Abbreviations: CT, choroidal thickness; SLE, systemic lupus erythematosus.

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In this study, we compared the CT of SLE patients without ophthalmological manifestations with a healthy control group. We observed an overall decrease in the CT of SLE patients in the central subfoveal choroid and the nasal, temporal and superior quadrants. In the inferior quadrants, SLE patients presented a thicker choroid. However, these differences did not reach statistical signif-icance. Moreover, the normal pattern of CT was observed in the control group with a thicker superior quadrant than the inferior and a thicker temporal quadrant than the nasal.24,25 In the SLE group, the temporal-nasal relation-ship was preserved, but the superior-inferior relationrelation-ship was reversed. In addition, normal progressive decrease of CT from the center to the periphery25was preserved in the horizontal meridian but lost in the vertical meridian in the SLE group, suggesting a ﬂatter and less reactive choroid.

Previous studies on the CT of SLE presented con flict-ing results. Altinkaynak et al reported a series of SLE with a statistically significant decrease in CT.13 However, this study only included patients in the “inactive” state and only measured the choroid in 3 locations: subfoveally, 1500 µm nasally and 1500 µm temporally from the foveal center. Given the irregularity of the chorioscleral border, measuring CT in more locations significantly increases the consistency of the results. Additionally, systemic factors, such as medication, the presence of lupus nephritis, NP-SLE, anti-phospholipid syndrome or other systemic comorbidities, were not included in the analysis. Ferreira et al published a series of SLE patients who had thicker choroids than healthy controls.14 However, this was a retrospective study performed in patients who performed SD-OCT in the context of a HCQ screening program. Therefore, disease activity status, blood pressure at the time of the examination and SLE-related systemic comor-bidities were not included in the analysis. In addition, CT was only measured in the horizontal foveal meridian. Agin et al in a study on juvenile SLE and Braga et al in a study on adult SLE patients described an increase in CT com-pared to healthy controls. However, none of these studies included multivariable analysis, and the effects of ocular and systemic variables known to influence CT, namely, axial length, spherical equivalent, IOP, blood pressure, BMI or systemic medication, were not taken into consid-eration in their analysis.15,16

In our study, we included 68 eyes of 68 SLE patients, and only one eye per patient was randomly selected for the study. All patients underwent a complete ophthalmologic evaluation previous to the exam as well as an appointment 500 400 300 200 CT - Subfoveal (μm) 100 0 0 10 20 30

Disease duration (years)

40 50 60

Figure 2 Association between choroidal thickness (CT) and disease duration in the systemic lupus erythematosus group.

500

Control group _{SLE group}

400 300 CT - nasal 500 μm CT - nasal 500 μm 200 100 200 300 400 500 600 60 70 80 90 MAP (mmHg) 100 110 120 60 70 80 90 MAP (mmHg) 100 110 120

Figure 3 Association between choroidal thickness (CT) and mean arterial pressure (MAP) in the control and systemic lupus erythematosus (SLE) groups.

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with an autoimmune disease specialist to assess disease activity and systemic comorbidities. In the multivariable analysis, after correcting for gender, age, BMI, MAP, BCVA, IOP, spherical equivalent, axial length and medica-tion, CT comparison between SLE and controls showed that CT was lower in the SLE group for all locations, except in the inferior 1000 and 1500 µm locations. CT was also negatively associated with age and axial length independently from the group, which is consistent with the literature.26–29 In some locations, there was a negative association between MAP and CT, which is consistent with previous studies.30,31 A higher BMI was also asso-ciated with a reduction in CT in some of the locations, and this relation was previously reported.32,33

In the multivariable regression analysis for the SLE group alone, in addition to age and axial length, antic-oagulants presented a negative association with CT in some locations. This association may represent a subset of SLE patients in whom the ischemic and atrophic pro-cess of the choroidal vasculature is more advanced. The subgroup of SLE patients with Sjogren’s syndrome pre-sented a thicker choroid in the 1000 µm superior location. This finding was not described previously; however, it should be interpreted with caution since onlyfive patients in our sample had the diagnosis of secondary Sjogren’s syndrome. Unlike Altinkaynak et al, we did not find a significant relation between choroidal thickness and dis-ease duration.13 However, when we analyze the scatter plot for disease duration, there seems to be a tendency for CT reduction after 20 years of disease. Finally, biopsy-proven lupus nephritis revealed a significant negative asso-ciation with CT in some of the locations. Subtle changes in choroidal circulation in SLE patients with nephropathy and no other signs of ophthalmic involvement was pre-viously demonstrated with indocyanine green angiography.8,34 However, to our knowledge, this is the first study to demonstrate a reduction of CT with SD-OCT in patients with lupus nephritis. This interestingfinding is of utmost importance as it may reflect the burden of systemic microvascular damage, particularly at the renal vasculature. The relation between the duration or cumula-tive dosage of HCQ and CT has provided inconsistent results in previous publications.14,35 In our study, we did not observe a significant association between HCQ treat-ment duration or cumulative dosage and CT.

Histopathology studies of the choroid in SLE patients have demonstrated mononuclear inﬂammatory cells within the choroid, reﬂecting choroidal vasculitis as well as

immunoglobulin and complement deposition in the chor-oidal vasculature.6,36 Consequently, choroidal blood sup-ply is compromised, leading to choroidal thinning. Chronic ischemia induces long-term atrophy of choroidal stromal, which also leads to choroidal thinning.37 These physiopathologic events may justify the decrease in CT of SLE patients and the loss of the normal topographic CT distribution observed in our study. This decrease in CT was more obvious in patients taking anticoagulants and patients with biopsy-proven lupus nephritis. In these sub-sets of patients, the prothrombotic and inflammatory state of repeated flares and long-term disease results in a pro-longed insult to choroidal vasculature that ultimately leads to choroidal atrophy. As a matter of fact, patients with lupus nephritis present a significantly increased risk of carotid atherosclerotic plaques, myocardial infarction and cardiovascular disease mortality than nonnephritis SLE patients and healthy controls.38,39

The results of this study also point to a defective vascular autoregulation in the choroid of SLE patients. Choroidal blood flow (BF) is a function of perfusion pressure (PP) and vascular radius (r): BF = PP/r. PP sub-sequently depends on arterial blood pressure and IOP.40 The main resistance to choroidal BF is located in choroidal arterioles. As stated before, choroidal BF is higher than that noted in most tissues with estimates ranging from 500 to 2000 ml/min/100 g tissue.41,42 Several studies suggest the existence of autoregulation in choroidal BF, which offsetsfluctuations in blood pressure and IOP.43–45 Some of the proposed vasoregulatory mechanisms include nitric oxide, endothelins, prostaglandins and the autonomic ner-vous system.46–50In our study, CT decreased with increas-ing MAP in healthy controls. On the other hand, CT in SLE patients remained unchanged throughout the entire range of MAP in the 13 studied locations. This behavior is probably related to defective mechanisms of blood flow regulation in response to changes in ocular perfusion pres-sure. In fact, autonomic dysfunction has been largely demonstrated in SLE patients, even in patients without manifest peripheral neuropathy, and there seems to be no relationship with disease duration, disease activity or dis-ease damage.51 Moreover, a high rate of endothelial dys-function and vascular stiffness has been reported in patients with early SLE, even without cardiovascular risk factors and disease.52

Our study has some limitations. First, CT measure-ments were manually obtained. Nevertheless, this manual technique has proven to have high intraobserver and

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interobserver reproducibility.53 Second, hydration status, which may affect the CT, was not taken into account. To minimize this issue, we managed to decrease any circadian variability by performing all measurements at the same time of the day and in the same environment.

Conclusion

In summary, this study using SD-OCT to evaluate the chor-oid in SLE has the largest sample in the literature and was the first to evaluate the effect of systemic comorbidities in the CT of SLE patients. We documented a generalized thinning of the choroid in SLE patients, except in the inferior quadrants. This pattern is associated with a loss of normal CT topo-graphic distribution in these patients. Moreover, a significant decrease in CT was observed in SLE patients taking antic-oagulants and those with lupus nephritis. A different response of CT to variations in MAP was also observed in SLE patients compared to healthy controls. These results probably reflect existing atrophy of choroidal tissue as well as defective vascular autoregulatory mechanisms. These findings may contribute to a better understanding of the pathogenesis of SLE choroidopathy and its associations with systemic vasculopathy. Further studies, with a long-itudinal design and Doppler blood flow analysis may con-tribute to a better understanding of our findings and the alterations occurring in the choroid as the disease progresses.

Acknowledgments

The content of this manuscript was accepted for oral pre-sentation at the 19th EURETINA Congress in Paris in September 2019. A grant for this study was given by José de Mello Saúde – Hospital CUF Descobertas. The authors have no commercial associations.

Disclosure

The authors report no conﬂicts of interest in this work.

References

1. Bugała K, Mazurek A, Gryga K, et al. Inﬂuence of autoimmunity and inﬂammation on endothelial function and thrombosis in systemic lupus erythematosus patients. Clin Rheumatol. 2018. doi:10.1007/s10067-018-4104-4

2. Taraborelli M, Sciatti E, Bonadei I, et al. Endothelial dysfunction in early systemic lupus erythematosus patients and controls without pre-vious cardiovascular events. Arthritis Care Res (Hoboken). 2017. doi:10.1002/acr.23495

3. Alam MM, Das P, Ghosh P, et al. Cardiovascular autonomic neuropathy in systemic lupus erythematosus. Indian J Physiol Pharmacol.2015;59 (2):155–161.

4. Liu Y, Kaplan MJ. Cardiovascular disease in systemic lupus erythe-matosus: an update. Curr Opin Rheumatol. 2018. doi:10.1097/ BOR.0000000000000528

5. Silpa-Archa S, Lee JJ, Foster CS. Ocular manifestations in systemic lupus erythematosus. Br J Ophthalmol. 2016;100(1):135–141. doi:10.1136/bjophthalmol-2015-306629

6. Dias-Santos A, Proença RP, Tavares Ferreira J, et al. The role of ophthalmic imaging in central nervous system degeneration in sys-temic lupus erythematosus. Autoimmun Rev. 2018:617–624. doi:10.1016/j.autrev.2018.01.011

7. Palejwala NV, Walia HS, Yeh S. Ocular manifestations of systemic lupus erythematosus: a review of the literature. Autoimmune Dis.

2012;1:1. doi:10.1155/2012/290898

8. Baglio V, Gharbiya M, Balacco-Gabrieli C, et al. Choroidopathy in patients with systemic lupus erythematosus with or without nephro-pathy. J Nephrol.2011;24(4):522–529. doi:10.5301/JN.2011.6244 9. Spaide RF, Koizumi H, Pozonni MC. Enhanced depth imaging

spec-tral-domain optical coherence tomography. Am J Ophthalmol.

2008;146(4):496–500. doi:10.1016/j.ajo.2008.05.032

10. Wood A, Binns A, Margrain T, et al. Retinal and choroidal thickness in early age-related macular degeneration. Am J Ophthalmol.2011. doi:10.1016/j.ajo.2011.05.021

11. Tan KA, Gupta P, Agarwal A, et al. State of science: choroidal thickness and systemic health. Surv Ophthalmol.2016. doi:10.1016/ j.survophthal.2016.02.007

12. Dias-Santos A, Ferreira J, Abegão Pinto L, et al. Choroidal thickness in nonarteritic anterior ischaemic optic neuropathy: a study with optical coherence tomography. Neuro-Ophthalmology. 2014;38:4. doi:10.3109/01658107.2014.926943

13. Altinkaynak H, Duru N, Uysal BS, et al. Choroidal thickness in patients with systemic lupus erythematosus analyzed by spectral-domain optical coherence tomography. Ocul Immunol Inﬂamm.

2015:1–7. doi:10.3109/09273948.2015.1006790

14. Ferreira CS, Beato J, Falcão MS, Brandão E, Falcão-Reis FCÂ. Choroidal thickness in multisystemic autoimmune diseases without ophthalmologic manifestations. Retina. 2017;37(3):529–535. doi:10.1097/IAE.0000000000001193

15. Braga J, Rothwell R, Oliveira M, et al. Choroid thickness proﬁle in patients with lupus nephritis. Lupus. 2019. doi:10.1177/ 0961203319828525

16. Ağın A, Kadayıfçılar S, Sönmez HE, et al. Evaluation of choroidal thickness, choroidal vascularity index and peripapillary retinal nerve ﬁber layer in patients with juvenile systemic lupus erythematosus. Lupus.2019. doi:10.1177/0961203318814196

17. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classiﬁcation of systemic lupus erythematosus. Arthritis Rheum.1997. doi:10.1002/art.1780400928

18. Marmor MF, Kellner U, Lai TYY, Melles RB, Mieler WF, Lum F. Recommendations on screening for chloroquine and hydroxychloro-quine retinopathy (2016 revision). Ophthalmology. 2016;123 (6):1386–1394. doi:10.1016/j.ophtha.2016.01.058

19. Bombardier C, Gladman DD, Urowitz MB, et al. Derivation of the sledai. A disease activity index for lupus patients. Arthritis Rheum.

1992. doi:10.1002/art.1780350606

20. Alm ABA. Ocular and optic nerve blood ﬂow at normal and increased intraocular pressures in monkeys (Macaca irus): a study with radioactively labelled microspheres includingﬂow determina-tions in brain and some other tissues. Exp Eye Res.1973;15:15–29. doi:10.1016/0014-4835(73)90185-1

21. Akay F, Gundogan FC, Yolcu U, Toyran S, Uzun S. Choroidal thickness in systemic arterial hypertension. Eur J Ophthalmol.

2015. doi:10.5301/ejo.5000675

22. Tavares Ferreira J, Vicente A, Proença R, et al. Choroidal thickness in diabetic patients without diabetic retinopathy. Retina. 2018. doi:10.1097/IAE.0000000000001582

(12)

23. Ahmad M, Kaszubski PA, Cobbs L, Reynolds H, Smith RT. Choroidal thickness in patients with coronary artery disease. PLoS One.2017. doi:10.1371/journal.pone.0175691

24. Esmaeelpour M, Považay B, Hermann B, et al. Three-dimensional 1060-nm OCT: choroidal thickness maps in normal subjects and improved posterior segment visualization in cataract patients. Investig Ophthalmol Vis Sci.2010. doi:10.1167/iovs.10-5196 25. Ikuno Y, Kawaguchi K, Nouchi T, Yasuno Y. Choroidal thickness in

healthy Japanese subjects RID F-2586-2011. Invest Ophthalmol Vis Sci.2010. doi:10.1167/iovs.09-4383

26. Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol.2016. doi:10.1016/j.ajo.2008.12.008

27. Ouyang Y, Heussen FM, Mokwa N, et al. Spatial distribution of posterior pole choroidal thickness by spectral domain optical coher-ence tomography. Investig Ophthalmol Vis Sci.2011. doi:10.1167/ iovs.11-8046

28. Li XQ, Larsen M, Munch IC. Subfoveal choroidal thickness in relation to sex and axial length in 93 Danish university students. Investig Ophthalmol Vis Sci.2011. doi:10.1167/iovs.11-8108 29. Barteselli G, Chhablani J, El-Emam S, et al. Choroidal volume

variations with age, axial length, and sex in healthy subjects: a three-dimensional analysis. Ophthalmology. 2012. doi:10.1016/j. ophtha.2012.06.065

30. Alm A. The effect of sympathetic stimulation on bloodﬂow through the uvea, retina and optic nerve in monkeys (Macaca irus). Exp Eye Res.1977. doi:10.1016/0014-4835(77)90241-X

31. Alm A, Bill A. The effect of stimulation of the cervical sympathetic chain on retinal oxygen tension and on uveal, retinal and cerebral blood ﬂow in cats. Acta Physiol Scand.1973. doi:10.1111/j.1748-1716.1973.tb05436.x

32. Öner Rİ, Karadağ AS. Evaluation of choroidal perfusion changes in obese patients: ocular effects of insulin resistance. Arq Bras Oftalmol.

2018;81(6):461–465.

33. Yilmaz I, Ozkaya A, Kocamaz M, et al. Correlation of choroidal thickness and body mass index. Retina. 2015. doi:10.1097/ IAE.0000000000000582

34. Gharbiya M, Pecci G, Baglio V, Gargiulo A, Allievi F, Balacco-Gabrieli C. Indocyanine green angiographic ﬁndings for patients with systemic lupus erythematosus nephropathy. Retina. 2006;26 (2):159–164. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 16467671.

35. Ahn SJ, Ryu SJ, Joung JY, Lee BR. Choroidal thinning associated with hydroxychloroquine retinopathy. Am J Ophthalmol. 2017. doi:10.1016/j.ajo.2017.08.022

36. Nag TC, Wadhwa S. Histopathological changes in the eyes in sys-temic lupus erythematosus: an electron microscope and immunohis-tochemical study. Histol Histopathol.2005. doi:10.14670/HH-20.373 37. Nag TC, Wadhwa S. Vascular changes of the retina and choroid in systemic lupus erythematosus: pathology and pathogenesis. Curr Neurovasc Res.2006. doi:10.2174/156720206776875821

38. Hermansen ML, Lindhardsen J, Torp-Pedersen C, Faurschou M, Jacobsen S. The risk of cardiovascular morbidity and cardiovascular mortality in systemic lupus erythematosus and lupus nephritis: a Danish nationwide population-based cohort study. Rheumatol.2017. doi:10.1093/rheumatology/kew475

39. Gustafsson JT, Herlitz Lindberg M, Gunnarsson I, et al. Excess atherosclerosis in systemic lupus erythematosus, - A matter of renal involvement: case control study of 281 SLE patients and 281 indivi-dually matched population controls. PLoS One.2017. doi:10.1371/ journal.pone.0174572

40. Riva CE, Alm A, Pournaras C. Ocular Circulation. In: Levin LA, Nilsson SFE, Ver HJ, Wu SM, Kaufman PL, Alm A, editors. Adler’s Physiology of the Eye. 11th ed. Edingburg: Saunders/Elsevier;2011:243–273. 41. Yu DY, Alder VA, Cringle SJ, Brown MJ. Choroidal bloodﬂow measured

in the dog eye in vivo and in vitro by local hydrogen clearance polaro-graphy: validation of a technique and response to raised intraocular pressure. Exp Eye Res.1988. doi:10.1016/S0014-4835(88)80021-6 42. Bill A. Blood circulation andﬂuid dynamics in the eye. Physiol Rev.

1975. doi:10.1152/physrev.1975.55.3.383

43. Polska E, Simader C, Weigert G, et al. Regulation of choroidal blood ﬂow during combined changes in intraocular pressure and arterial blood pressure. Ophthalmol Vis Sci. 2007;48:3768–3774. doi:10.1167/iovs.07-0307

44. Riva CE, Titze P, Hero M, Petrig BL. Effect of acute decreases of perfusion pressure on choroidal blood ﬂow in humans. Investig Ophthalmol Vis Sci.1997;38(9):1752–1760.

45. Riva CE, Titze P, Hero M, Movaffaghy A, Petrig BL. Choroidal bloodﬂow during isometric exercises. Investig Ophthalmol Vis Sci.

1997;38(11):2338–2343.

46. Simader C, Lung S, Weigert G, et al. Role of NO in the control of choroidal bloodﬂow during a decrease in ocular perfusion pressure. Invest Ophthalmol Vis Sci.2009. doi:10.1167/iovs.07-1614 47. Schmetterer L, Polak K. Role of nitric oxide in the control of ocular blood

ﬂow. Prog Retin Eye Res.2001. doi:10.1016/S1350-9462(01)00014-3 48. Kiel JW. Endothelin modulation of choroidal bloodﬂow in the rabbit.

Exp Eye Res.2000. doi:10.1006/exer.2000.0911

49. Chemtob S, Beharry K, Rex J, Chatterjee T, Varma DR, Aranda JV. Ibuprofen enhances retinal and choroidal bloodﬂow autoregulation in newborn piglets. Investig Ophthalmol Vis Sci.1991;32(6):1799–1807. 50. Steinle JJ, Krizsan-Agbas D, Smith PG. Regional regulation of

choroi-dal bloodﬂow by autonomic innervation in the rat. Am J Physiol Regul Integr Comp Physiol.2000. doi:10.1152/ajpregu.2000.279.1.R202 51. Shalimar HR, Deepak KK, Bhatia M, Aggarwal P, Pandey RM.

Autonomic dysfunction in systemic lupus erythematosus. Rheumatol Int.2006. doi:10.1007/s00296-005-0093-0

52. Taraborelli M, Sciatti E, Bonadei I, et al. Endothelial dysfunction in early systemic lupus erythematosus patients and controls without previous cardiovascular events. Arthritis Care Res.2018. doi:10.1002/acr.23495 53. Shao L, Xu L, Chen CX, et al. Reproducibility of subfoveal choroidal

thickness measurements with enhanced depth imaging by spectral-domain optical coherence tomography. Investig Ophthalmol Vis Sci.

2013. doi:10.1167/iovs.12-10351

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